Platinum anticancer agents in the clinic today are potent and efficacious; however, they cause a large number of serious adverse effects because their activity is often not targeted at the cancer, but rather, at all body tissues with the cancerous tissue being included. This invention addresses these and other needs in the art. For example, provided herein is a means to channel the activity of a platinum anticancer agent to a cancerous tissue, thereby decreasing the potential of adverse effects.
Cancer is the second leading cause of death behind heart disease. In fact, cancer incidence and death figures account for about 10% of the U.S. population in certain areas of the United States (National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database and Bureau of the Census statistics; see, Harrison's Principles of Internal Medicine, Kasper et al., 16th ed., 2005, Chapter 66). The five leading causes of cancer deaths among men are lung cancer, prostate cancer, colon and rectum cancer, pancreatic cancer, and leukemia. The five leading causes of cancer deaths among women are lung cancer, breast cancer, colon cancer, ovarian cancer, and pancreatic cancer. When detected at locally advanced or metastatic stages, no consistently curative treatment regimen exists. Treatment for metastatic cancer includes immunotherapy, hormonal ablation, radiation therapy, chemotherapy, hormonal therapy, and combination therapies. Unfortunately, for prostate cancer and hormone dependent tumors, there is frequent relapse of an aggressive androgen independent disease that is insensitive to further hormonal manipulation or to treatment with conventional chemotherapy (Ghosh et al., Proc. Natl. Acad. Sci. U.S.A., 95:13182-13187 (1998)).
The organic cation transporters (OCTs), OCT1 (Grundemann et al., Nature, 372:549-552 (1994)), OCT2 (Okuda et al., Biochem. Biophys. Res. Comm., 224:500-507 (1996)), and OCT3 (Kekuda et al., J. Biol. Chem., 273:15971-15979 (1998); Wu et al., J. Biol. Chem., 273:32776-32786 (1998)), are in the class of plasma membrane transporters belonging to the solute carrier (SLC) 22A family. The OCTs mediate intracellular uptake of a broad range of structurally diverse organic cations (Jonker et al., J. Pharmacol. Exp. Ther., 308:2-9 (2004); Wright, Toxicol. Appl. Pharmacol., 204:309-319 (2005)). Substrates of OCTs include endogenous compounds such as choline, creatinine, and monoamine neurotransmitters, and a variety of xenobiotics such as tetraethylammonium (TEA, a prototypic organic cation), 1-methyl-4-phenylpyridinium (MPP+, a neurotoxin) and clinically used drugs such as metformin, cimetidine, and amantadine (Jonker et al., supra). In humans, OCT1 is primarily expressed in the liver (Gorboulev et al., DNA Cell Biol., 16:871-881 (1997); Zhang et al., Mol. Pharmacol., 51:913-921 (1997); Wright, supra) and less so in the intestine (Muller et al., Biochem. Pharmacol., 70:1851-1860 (2005)), whereas OCT2 is predominantly expressed in the kidney (Gorboulev et al., supra; Wright, supra). OCT3 is expressed in many tissues including placenta, heart, liver, and skeletal muscle (Grundemann et al., Nat. Neurosci., 1:349-351 (1998); Verhaagh et al., Genomics, 55:209-218 (1999)). The expression of the OCTs has also been detected in a number of human cancer cell lines (Hayer-Zillgen et al., Br. J. Pharmacol., 136:829-836 (2002)). The interaction of cisplatin with human OCTs has been investigated and the results are discordant (Briz et al., Mol. Pharmacol., 61:853-860 (2002); Ciarimboli et al., Am. J. Pathol., 167:1477-1484 (2005)). Previous studies indicate that cisplatin is not a substrate of human OCT1 or OCT2 (Briz et al., supra), whereas more recent work indicates that the drug interacts with human and rat OCT2 but not OCT1 (Ciarimboli et al., supra; Yonezawa et al., Biochem. Pharmacol., 70:1823-1831 (2005)).
Platinum-based compounds and drugs are among the most active anticancer agents and cisplatin represents one of the three most widely used cancer chemotherapeutics (Wong et al., Chem. Rev., 99:2451-2466 (1999)). Although cisplatin is effective against a number of solid tumors, especially testicular and ovarian cancer, its clinical use is limited because of its toxic effects as well as the intrinsic and acquired resistance of some tumors to this drug (Weiss et al., Drugs, 46:360-377 (1993)). Carboplatin is less nephrotoxic, but its cross-resistance with cisplatin limits its application in otherwise cisplatin-treatable diseases (Weiss et al., supra). Oxaliplatin, however, exhibits a different anticancer spectrum from that of cisplatin (Raymond et al., Ann. Oncol., 9:1053-1071 (1998); Rixe et al., Biochem. Pharmacol., 52:1855-1865 (1996)). It has been approved as the first or second line therapy in combination with 5-fluoruracil/leucovorin for advanced colorectal cancer, for which cisplatin and carboplatin are essentially inactive (Misset et al., Crit. Rev. Oncol. Hematol., 35:75-93 (2000)). In spite of their distinct antitumor specificities, cisplatin and oxaliplatin exhibit cytotoxicity (Pinto et al., Biochim. Biophys. Acta, 780:167-180 (1985); Zamble et al., Trends Biochem. Sci., 20:435-439 (1995)). These compounds may initiate a series of biochemical cascades, eventually leading to cell death (Pinto et al., supra; Wang et al., Nat. Rev. Drug Discov., 4:307-320 (2005)).
Cisplatin and oxaliplatin target similar DNA sites for binding and form similar types of DNA adducts (Jennerwein et al., Chem. Biol. Interact., 70:39-49 (1989); Page et al., Biochemistry, 29:1016-1024 (1990); Woynarowski et al., Mol. Pharmacol., 54:770-777 (1998)), mainly 1,2- and 1,3-intrastrand cross-links involving purine nucleotides. Studies aiming to identify such mechanisms have focused on the cellular processing of cisplatin- and oxaliplatin-DNA adducts (Chaney et al., Crit. Rev. Oncol. Hematol., 53:3-11 (2005); Vaisman et al., Biochemistry, 38:11026-11039 (1999)). Reduced intracellular accumulation is a common observation in cisplatin-resistant cells (Andrews et al., Cancer Cells, 2:35-43 (1990); Gately et al., Br. J. Cancer, 67:1171-1176 (1993)).